Pneumocystis jirovecii: Difference between revisions

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Pneumocystis jirovecii
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βˆ’
* Opportunistic fungal infection of the lower respiratory infection
 +
*Opportunistic fungal infection of the lower respiratory infection
   
βˆ’
== Microbiology ==
 +
==Background==
  +
===Microbiology===
   
βˆ’
* Yeast-like fungus in the Ascomycota phylum
 +
*Yeast-like fungus in the [[Phylum::Ascomycota]] phylum
βˆ’
* Has not been able to be grown in culture, and species within the genus have tropism for their specific host
 +
*Has not been able to be grown in culture, and species within the genus have tropism for their specific host
βˆ’
* It's cell wall lacks ergosterol, so has inherent resistance to many antifungals
 +
*It's cell wall lacks ergosterol, so has inherent resistance to many antifungals
βˆ’
* Ξ²-1,3 glucan, however, is an important cell wall component
 +
*Ξ²-1,3 glucan, however, is an important cell wall component
βˆ’
* The major immunogenic protein is major surface glycoprotein (Msg), or gpA
 +
*The major immunogenic protein is major surface glycoprotein (Msg), or gpA
   
βˆ’
=== History ===
 +
===History===
   
βˆ’
* ''P. jirovecii'' was previously thought to be ''P. carinii'', but it was later realized that they were two species within the same genus
 +
*''P. jirovecii'' was previously thought to be ''P. carinii'', but it was later realized that they were two species within the same genus
βˆ’
** ''P. carinii'' and ''P. wakefieldiae'' infect rats, ''P. murina'' infects mice and ''P. jiroveci'' infects humans
 +
**''P. carinii'' and ''P. wakefieldiae'' infect rats, ''P. murina'' infects mice and ''P. jiroveci'' infects humans
βˆ’
* Also previously thought to be a protozoan, but reclassified as fungus based on phylogenetic analysis, most closely related to ''Schizosaccharomyces pombe''
 +
*Also previously thought to be a protozoan, but reclassified as fungus based on phylogenetic analysis, most closely related to ''Schizosaccharomyces pombe''
   
βˆ’
== Epidemiology ==
 +
===Epidemiology===
   
βˆ’
* Worldwide distribution
 +
*Worldwide distribution
  +
**May be environmental, associated with outdoor activities and spaces (but not clear)
βˆ’
* Only circulates within humans
  
  +
**Human-to-human transmission is possible
βˆ’
* Most children have been exposed by age 2 or 3
  
  +
*Only circulates within humans, with reservoirs including children and immunocompromised patients
βˆ’
* Children and immunocompromised patients being the reservoir
  
  +
**Primary infection occurs in infants, who are likely the natural host; most have been exposed by 2-3 years of age
βˆ’
** Includes asymptomatic carriage by patients with HIV, malignancy, and long-term steroid use, and in pregnant women
  
  +
**Includes asymptomatic carriage by patients with HIV, malignancy, and long-term steroid use, and in pregnant women
βˆ’
* Risk factors for infection:
  
  +
*Colonization is common, associated with the following:
βˆ’
** HIV
  
  +
**Immunosuppressive conditions (HIV, low CD4 cell count, cancer, autoimmune diseases, organ transplantation)
βˆ’
** Immune-suppression, e.g. from steroids
  
  +
**Immunosuppressive drugs (corticosteroids, TNF-Ξ± inhibitors)
  +
**COPD and other chronic lung disorders
  +
**Other conditions (pregnancy, cigarette smoking)
  +
**Lack of surfactant
  +
**But also 20% of healthy people
  +
*Infection is mostly associated with HIV
  +
**Much higher risk with HIV/AIDS with low CD4 count <200
  +
**More common in Asian and South/Central America
  +
*Infection is still possible in immunocompetent hosts
  +
**TNF-alpha inhibitors, B-cell inhibitors, and corticosteroid use
   
βˆ’
== Pathophysiology ==
 +
===Pathophysiology===
   
βˆ’
* After inhalation of cyst, trophic forms are released and adhere to type I pneumocytes in the alveolar epithelium
 +
*After inhalation of cyst, trophic forms are released and adhere to type I pneumocytes in the alveolar epithelium
βˆ’
* The immune response involves a combination of humoral and cell-mediated immunity
 +
*The immune response involves a combination of humoral and cell-mediated immunity
βˆ’
** Alveolar macrophages are the first response, but require CD4 cells to respond fully
 +
**Alveolar macrophages are the first response, but require CD4 cells to respond fully
βˆ’
** IgM antibodies recognize common fungal carbohydrate antigens
 +
**IgM antibodies recognize common fungal carbohydrate antigens
βˆ’
** CD4 cells are important for the memory response
 +
**CD4 cells are important for the memory response
βˆ’
* The alveolus fills with ''Pneumocystis''
 +
*The alveolus fills with ''Pneumocystis''
βˆ’
* The inflammatory response may damage the lung
 +
*The inflammatory response may damage the lung
   
βˆ’
== Clinical Presentation ==
 +
==Clinical Manifestations==
  +
===Infants===
   
  +
*Interstitial plasma cell pneumonia between 6 weeks and 4 months
βˆ’
=== Infants ===
  
  +
*Typically in orphanages under crowded conditions
  +
*Insidious onset with poor feeding, progressing to cyanosis
   
  +
===Adults===
βˆ’
* Interstitial plasma cell pneumonia between 6 weeks and 4 months
  
βˆ’
* Typically in orphanages under crowded conditions
  
βˆ’
* Insidious onset with poor feeding, progressing to cyanosis
  
   
  +
*Worsening exertional dyspnea, fever, and non-productive cough
βˆ’
=== Adults ===
  
  +
**Symptoms usually more insidious in severe HIV
  +
**Symptoms may develop after tapering immunosupressive drugs like steroids
  +
*Tachypnea and tachycardia with exertional hypoxemia
  +
*CXR may initially be normal, then progresses to whiteout
  +
**Can also show unilateral consolidation, nodules, cysts, pneumatoceles, mediastinal lymphadenopathy, and pleural effusions
  +
*High LDH from lung damage
  +
*In advanced HIV, can disseminate to lymph nodes, spleen, liver, bone marrow, GI tract, eyes, thyroid, adrenal glands, and kidneys
   
  +
==Investigations==
βˆ’
* Worsening exertional dyspnea, fever, and non-productive cough
  
βˆ’
** Symptoms usually more insidious in severe HIV
  
βˆ’
** Symptoms may develop after tapering immunosupressive drugs like steroids
  
βˆ’
* Tachypnea and tachycardia with exertional hypoxemia
  
βˆ’
* CXR may initially be normal, then progresses to whiteout
  
βˆ’
** Can also show unilateral consolidation, nodules, cysts, pneumatoceles, mediastinal lymphadenopathy, and pleural effusions
  
βˆ’
* High LDH from lung damage
  
βˆ’
* In advanced HIV, can disseminate to lymph nodes, spleen, liver, bone marrow, GI tract, eyes, thyroid, adrenal glands, and kidneys
  
   
  +
*CXR
βˆ’
== Investigations ==
  
  +
**Typical: bilateral diffuse patchy disease
  +
**Atypical:
  +
***Normal (15%)
  +
***Localized
  +
***Pneumothorax
  +
***Upper lobe, if on pentamidine
  +
*6min walk test: will desaturate, even if well-oxygenated at rest
  +
*LDH increased, though it has an LR+ of 1.5 and LR– of 0.61, so neither sensitive nor specific
  +
*CBC often normal
   
  +
==Diagnosis==
βˆ’
* CXR
  
βˆ’
* Typical: bilateral diffuse patchy disease
  
βˆ’
* Atypical:
  
βˆ’
** Normal (15%)
  
βˆ’
** Localized
  
βˆ’
** Pneumothorax
  
βˆ’
** Upper lobe, if on pentamidine
  
βˆ’
* LDH increased
  
βˆ’
* CBC often normal
  
   
  +
*Cannot be cultured
βˆ’
== Diagnosis ==
  
  +
*Specimens include sputum (best), BAL, or biopsy
  +
**Test characteristics of non-invasive (i.e. non-BAL) samples are summarized in [[CiteRef::senΓ©cal2022no]]
  +
*Microscopy
  +
**The gold standard
  +
**Direct fluorescent antibody (DFA) staining from induced sputum or BAL (about 75% sensitive from sputum)
  +
**Can also use Gomori Methenamine-Silver or Diff-Quik staining
  +
*Molecular
  +
**PCR from induced sputum or BAL (about 99% sensitive)
  +
**Nasopharyngeal aspirate is about 90% sensitive
  +
**Whole serum is about 80% sensitivty and specific
  +
**Can detect lower burden of PJP, especially in immunocompetent hosts where it is likely not causing disease but is instead helping to circulate it among the population
  +
*Serology
  +
**Not sensitive or specific
  +
**1,3-Ξ²-D glucan levels may be elevated (Sn 95%, Sp 86%)
  +
***diagnostic accuracy was not different between HIV positive and HIV negative patients
  +
***Can be used as a screening tool
  +
***False positives with other IFIs, [[Candida]], IV [[amoxicillin-clavulanic acid]], treatment of patients with immunological preparations (albumins or globulins), use of cellulose membranes and filters made from cellulose in hemodialysis, and use of cotton gauze swabs/packs/pads and sponges during surgery
   
  +
==Management==
βˆ’
* Induced sputum or brochoalveolar lavage (normal sputum not sensitive enough)
  
βˆ’
* 6min walk test: will desaturate, even if well-oxygenated at rest
  
   
  +
*First-line: [[Is treated by::TMP-SMX]] 15-20 mg/kg IV or PO divided q6-8h
βˆ’
== Treatment ==
  
  +
**If mild-moderate, can give [[TMP-SMX]] DS 2 tabs PO tid
  +
*Alternatives:
  +
**[[Is treated by::Clindamycin]] 600-900 mg IV q6-8h with [[Is treated by::primaquine]] 15 to 30 mg PO daily
  +
**[[Is treated by::Pentamidine]] 4 mg/kg IV daily
  +
**[[Is treated by::Trimethoprim]] 15 mg/kg PO divided q8h with [[Is treated by::dapsone]] 100 mg PO daily
  +
**[[Is treated by::Atovaquone]] 750 mg PO bid (for mild-moderate only)
  +
**Possibly [[anidulafungin]][[CiteRef::chen2019an]]
  +
*Adjunctive: [[Prednisone]] 40 mg PO bid for 5 days, followed by 40 mg PO daily for 5 days, followed by 20 mg po daily for 11 days
  +
**Can use methylprednisolone at 75% of predisone dose
  +
**Typically indicated if PaO<sub>2</sub> ≀70 mmHg or A-a O<sub>2</sub> gradient &gt;35 mmHg
  +
*Duration is 21 days (3 weeks)
   
  +
==Prevention==
βˆ’
* First-line: [[TMP-SMX]] 15-20 mg/kg IV or PO divided q6-8h
  
βˆ’
** If mild-moderate, can give [[TMP-SMX]] DS 2 tabs PO tid
  
βˆ’
* Alternatives:
  
βˆ’
** [[Clindamycin]] 600-900 mg IV q6-8h with [[primaquine]] 15 to 30 mg PO daily
  
βˆ’
** [[Pentamidine]] 4 mg/kg IV daily
  
βˆ’
** Trimethoprim 15 mg/kg PO divided q8h with [[dapsone]] 100 mg PO daily
  
βˆ’
** [[Atovaquone]] 750 mg PO bid (for mild-moderate only)
  
βˆ’
* Adjunctive: [[Prednisone]] 40 mg PO bid for 5 days, followed by 40 mg PO daily for 5 days, followed by 20 mg po daily for 11 days
  
βˆ’
** Can use methylprednisolone at 75% of predisone dose
  
βˆ’
** Typically indicated if PaO<sub>2</sub> ≀70 mmHg or A-a O<sub>2</sub> gradient &gt;35 mmHg
  
βˆ’
* Duration is 21 days (3 weeks)
  
   
βˆ’
=== Prophylaxis ===
 +
===Prophylaxis===
   
  +
*Indicated in population with risk of PJP >3.5% per year
βˆ’
* Indications
  
  +
**'''HIV:''' prior ''Pneumocystis'' pneumonia; CD4 <200; oropharyngeal ''Candida'' regardless of CD4
βˆ’
** Medications: prenisolone β‰₯20 mg daily for >4 weeks; TNF-Ξ± inhibitors; steroids plus a steroid-sparing agent
  
  +
**'''Medications:''' [[prednisolone]] β‰₯20 mg daily for >4 weeks; TNF-Ξ± inhibitors; [[steroids]] plus a steroid-sparing agent
βˆ’
** Cancer treatment: steroids and cyclophosphamide; alemtuzumab for at least 2 months after treatment and until CD4 >200; temozolomide and radiation therapy, until CD4 >200; fludarabine and T-cell depletion, until CD4 >200; any antileukemic therapy
  
  +
**'''Cancer treatment:''' [[steroids]] and [[cyclophosphamide]]; [[alemtuzumab]] for at least 2 months after treatment and until CD4 >200; temozolomide and radiation therapy, until CD4 >200; [[fludarabine]] and T-cell depletion, until CD4 >200; any antileukemic therapy
βˆ’
** HIV: prior ''Pneumocystis'' pneumonia; CD4 <200; oropharyngeal ''Candida'' regardless of CD4
  
βˆ’
** Rheumatology treatment: GPA receiving cyclophosphamide, especially with steroids
 +
**'''Rheumatology treatment:''' GPA receiving [[cyclophosphamide]], especially with [[steroids]]
βˆ’
** Transplantation: [[allogeneic stem cell transplantation]] for at least 180 days; [[autologous stem cell transplantation]] for at least 3 to 6 months
 +
**'''Transplantation:''' [[allogeneic stem cell transplantation]] for at least 180 days; [[autologous stem cell transplantation]] for at least 3 to 6 months
βˆ’
** Primary immunodeficiency: [[SCID]]; idiopathic CD4 lymphocytopenia; [[hyper-IgM syndrome]]
 +
**'''Primary immunodeficiency:''' [[SCID]]; idiopathic CD4 lymphocytopenia; [[hyper-IgM syndrome]]
βˆ’
* First-line: [[TMP-SMX]] DS or SS 1 tab PO daily
 +
*First-line: [[TMP-SMX]] DS or SS 1 tab PO daily
βˆ’
* Alternatives:
 +
*Alternatives:
βˆ’
** [[TMP-SMX]] DS 1 tab po tiw
 +
**[[TMP-SMX]] DS 1 tab po tiw
βˆ’
** [[Dapsone]] 100 mg po daily, or 50 mg po bid
 +
**[[Dapsone]] 100 mg po daily, or 50 mg po bid
βˆ’
** [[Dapsone]] 50 mg po daily with [[pyrimethamine]] 50 mg po weekly and leucovorin 25 mg po weekly
 +
**[[Dapsone]] 50 mg po daily with [[pyrimethamine]] 50 mg po weekly and [[leucovorin]] 25 mg po weekly
βˆ’
** [[Pentamidine]] 300 mg inhaled monthly
 +
**[[Pentamidine]] 300 mg inhaled monthly
βˆ’
** [[Atovaquone]] 750 mg po bid or 1500 mg po daily
 +
**[[Atovaquone]] 1500 mg po daily (or 750 mg po bid)
βˆ’
** [[Atovaquone]] as above with [[pyrimethamine]] 25 mg po daily and leucovorin 10 mg po daily
 +
**[[Atovaquone]] as above with [[pyrimethamine]] 25 mg po daily and [[leucovorin]] 10 mg po daily
  +
*No consensus on when to stop prophylaxis
βˆ’
* Usually instituted if the risk of PJP is greater than 3.5% per year
  
  +
**Although there are no clear data guiding when to stop prophylaxis, it is probably reasonable to stop once the dose [[prednisone]] drops below 15-20 mg daily or equivalent
  +
**In patients with HIV, stopping once CD4 count is above 200 for 3 months
  +
**In patients receiving chemotherapy, at least one guideline recommends continuing for 6 weeks after the steroid-tapering period[[CiteRef::cooley2014co]]
  +
**For renal transplantation, AST guidelines recommend 6-12 months after transplantation and European guidelines recommend 4 months after transplantation[[CiteRef::goto2011pn]]
  +
  +
==Further Reading==
  +
  +
*''Pneumocystis'' Colonization Is Highly Prevalent in the Autopsied Lungs of the General Population. ''Clin Infect Dis''. 2010;50:347. doi: [https://doi.org/10.1086/649868 10.1086/649868]
  +
*Near-Universal Prevalence of ''Pneumocystis'' and Associated Increase in Mucus in the Lungs of Infants With Sudden Unexpected Death. ''Clin Infect Dis''. 2013;56:171. doi: [https://doi.org/10.1093/cid/cis870 10.1093/cid/cis870]
   
 
{{DISPLAYTITLE:''Pneumocystis jirovecii''}}
  
{{DISPLAYTITLE:''Pneumocystis jirovecii''}}

Latest revision as of 13:44, 27 December 2023

  • Opportunistic fungal infection of the lower respiratory infection

Background

Microbiology

  • Yeast-like fungus in the Ascomycota phylum
  • Has not been able to be grown in culture, and species within the genus have tropism for their specific host
  • It's cell wall lacks ergosterol, so has inherent resistance to many antifungals
  • Ξ²-1,3 glucan, however, is an important cell wall component
  • The major immunogenic protein is major surface glycoprotein (Msg), or gpA

History

  • P. jirovecii was previously thought to be P. carinii, but it was later realized that they were two species within the same genus
    • P. carinii and P. wakefieldiae infect rats, P. murina infects mice and P. jiroveci infects humans
  • Also previously thought to be a protozoan, but reclassified as fungus based on phylogenetic analysis, most closely related to Schizosaccharomyces pombe

Epidemiology

  • Worldwide distribution
    • May be environmental, associated with outdoor activities and spaces (but not clear)
    • Human-to-human transmission is possible
  • Only circulates within humans, with reservoirs including children and immunocompromised patients
    • Primary infection occurs in infants, who are likely the natural host; most have been exposed by 2-3 years of age
    • Includes asymptomatic carriage by patients with HIV, malignancy, and long-term steroid use, and in pregnant women
  • Colonization is common, associated with the following:
    • Immunosuppressive conditions (HIV, low CD4 cell count, cancer, autoimmune diseases, organ transplantation)
    • Immunosuppressive drugs (corticosteroids, TNF-Ξ± inhibitors)
    • COPD and other chronic lung disorders
    • Other conditions (pregnancy, cigarette smoking)
    • Lack of surfactant
    • But also 20% of healthy people
  • Infection is mostly associated with HIV
    • Much higher risk with HIV/AIDS with low CD4 count <200
    • More common in Asian and South/Central America
  • Infection is still possible in immunocompetent hosts
    • TNF-alpha inhibitors, B-cell inhibitors, and corticosteroid use

Pathophysiology

  • After inhalation of cyst, trophic forms are released and adhere to type I pneumocytes in the alveolar epithelium
  • The immune response involves a combination of humoral and cell-mediated immunity
    • Alveolar macrophages are the first response, but require CD4 cells to respond fully
    • IgM antibodies recognize common fungal carbohydrate antigens
    • CD4 cells are important for the memory response
  • The alveolus fills with Pneumocystis
  • The inflammatory response may damage the lung

Clinical Manifestations

Infants

  • Interstitial plasma cell pneumonia between 6 weeks and 4 months
  • Typically in orphanages under crowded conditions
  • Insidious onset with poor feeding, progressing to cyanosis

Adults

  • Worsening exertional dyspnea, fever, and non-productive cough
    • Symptoms usually more insidious in severe HIV
    • Symptoms may develop after tapering immunosupressive drugs like steroids
  • Tachypnea and tachycardia with exertional hypoxemia
  • CXR may initially be normal, then progresses to whiteout
    • Can also show unilateral consolidation, nodules, cysts, pneumatoceles, mediastinal lymphadenopathy, and pleural effusions
  • High LDH from lung damage
  • In advanced HIV, can disseminate to lymph nodes, spleen, liver, bone marrow, GI tract, eyes, thyroid, adrenal glands, and kidneys

Investigations

  • CXR
    • Typical: bilateral diffuse patchy disease
    • Atypical:
      • Normal (15%)
      • Localized
      • Pneumothorax
      • Upper lobe, if on pentamidine
  • 6min walk test: will desaturate, even if well-oxygenated at rest
  • LDH increased, though it has an LR+ of 1.5 and LR– of 0.61, so neither sensitive nor specific
  • CBC often normal

Diagnosis

  • Cannot be cultured
  • Specimens include sputum (best), BAL, or biopsy
    • Test characteristics of non-invasive (i.e. non-BAL) samples are summarized in 1
  • Microscopy
    • The gold standard
    • Direct fluorescent antibody (DFA) staining from induced sputum or BAL (about 75% sensitive from sputum)
    • Can also use Gomori Methenamine-Silver or Diff-Quik staining
  • Molecular
    • PCR from induced sputum or BAL (about 99% sensitive)
    • Nasopharyngeal aspirate is about 90% sensitive
    • Whole serum is about 80% sensitivty and specific
    • Can detect lower burden of PJP, especially in immunocompetent hosts where it is likely not causing disease but is instead helping to circulate it among the population
  • Serology
    • Not sensitive or specific
    • 1,3-Ξ²-D glucan levels may be elevated (Sn 95%, Sp 86%)
      • diagnostic accuracy was not different between HIV positive and HIV negative patients
      • Can be used as a screening tool
      • False positives with other IFIs, Candida, IV amoxicillin-clavulanic acid, treatment of patients with immunological preparations (albumins or globulins), use of cellulose membranes and filters made from cellulose in hemodialysis, and use of cotton gauze swabs/packs/pads and sponges during surgery

Management

  • First-line: TMP-SMX 15-20 mg/kg IV or PO divided q6-8h
    • If mild-moderate, can give TMP-SMX DS 2 tabs PO tid
  • Alternatives:
  • Adjunctive: Prednisone 40 mg PO bid for 5 days, followed by 40 mg PO daily for 5 days, followed by 20 mg po daily for 11 days
    • Can use methylprednisolone at 75% of predisone dose
    • Typically indicated if PaO2 ≀70 mmHg or A-a O2 gradient >35 mmHg
  • Duration is 21 days (3 weeks)

Prevention

Prophylaxis

  • Indicated in population with risk of PJP >3.5% per year
  • First-line: TMP-SMX DS or SS 1 tab PO daily
  • Alternatives:
  • No consensus on when to stop prophylaxis
    • Although there are no clear data guiding when to stop prophylaxis, it is probably reasonable to stop once the dose prednisone drops below 15-20 mg daily or equivalent
    • In patients with HIV, stopping once CD4 count is above 200 for 3 months
    • In patients receiving chemotherapy, at least one guideline recommends continuing for 6 weeks after the steroid-tapering period3
    • For renal transplantation, AST guidelines recommend 6-12 months after transplantation and European guidelines recommend 4 months after transplantation4

Further Reading

  • Pneumocystis Colonization Is Highly Prevalent in the Autopsied Lungs of the General Population. Clin Infect Dis. 2010;50:347. doi: 10.1086/649868
  • Near-Universal Prevalence of Pneumocystis and Associated Increase in Mucus in the Lungs of Infants With Sudden Unexpected Death. Clin Infect Dis. 2013;56:171. doi: 10.1093/cid/cis870

References

  1. ^  Po-Yi Chen, Chong-Jen Yu, Jung-Yien Chien, Po-Ren Hsueh. Anidulafungin as an alternative treatment for Pneumocystis jirovecii pneumonia in patients who could not tolerate Trimethoprim/sulfamethoxazole. International Journal of Antimicrobial Agents. 2019. doi:10.1016/j.ijantimicag.2019.10.001.
  2. ^  L. Cooley, C. Dendle, J. Wolf, B. W. Teh, S. C. Chen, C. Boutlis, K. A. Thursky. Consensus guidelines for diagnosis, prophylaxis and management ofPneumocystis jiroveciipneumonia in patients with haematological and solid malignancies, 2014. Internal Medicine Journal. 2014;44(12b):1350-1363. doi:10.1111/imj.12599.
  3. ^  N. Goto, S. Oka. Pneumocystis jirovecii pneumonia in kidney transplantation. Transplant Infectious Disease. 2011;13(6):551-558. doi:10.1111/j.1399-3062.2011.00691.x.

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